First-trimester use of antiseizure medications and the risk of miscarriage: a population-based cohort study

Abstract

Background: Antiseizure medications (ASMs) during the first trimester of pregnancy have been associated with an increased risk of miscarriage.

Methods: We carried out a population-based cohort study using routinely collected healthcare data from the UK, 1995-2018. Pregnancies were identified in the Clinical Practice Research Datalink and we estimated the HR of miscarriage associated with prescriptions of ASMs during the first trimester of pregnancy, using Cox regression, adjusting for potential confounders, including ASM indications.

Results: ASMs were prescribed during the first trimester in 7832 (0.8%) of 1 023 787 included pregnancies. 14.5% of pregnancies with first-trimester exposure to ASMs ended in miscarriage, while 12.2% without ASM exposure in the first trimester ended in miscarriage; after adjustment, there was a 1.06-fold relative hazard of miscarriage (95% CI 1.00 to 1.13) in women with first-trimester ASM use. After restricting to women with specific ASM indications, this association was not evident in women with epilepsy (adjusted HR 0.98, 95% CI 0.89 to 1.08), but was observed in women with bipolar or other psychiatric conditions (1.08, 95% CI 1.00 to 1.16) although CIs overlapped. Compared with discontinuation of ASMs prior to pregnancy, there was no evidence of increased risk of miscarriage for first-trimester ASM use in women with bipolar or other psychiatric conditions (1.02, 95% CI 0.87 to 1.20).

Conclusion: We found no clear evidence to suggest that first-trimester ASM use increased the risk of miscarriage. Taken together, our analyses suggest that apparent associations between first-trimester ASM use and miscarriage may be the result of confounding by the presence of a bipolar disorder or associated unmeasured variables.

Keywords: CLINICAL NEUROLOGY; OBSTETRICS; PSYCHIATRY.

Figure 1

Flow diagram of selected participants. ¹See online supplemental material for more information on how we dealt with uncertain pregnancies in the Clinical Practice Research Datalink Pregnancy Register. ²Conflicting pregnancies refer to pregnancies where dates overlap. ³Historical pregnancies refer to past pregnancies recorded at a later date. HES, Hospital Episode Statistics.

Figure 2

Number of miscarriages, total pregnancies and proportion with miscarriages, in exposed and unexposed and adjusted HRs of miscarriage associated with antiseizure medications treatment in the first trimester of pregnancy, overall and stratified by ASM indication. *Adjusted for maternal age, year of pregnancy start, Index of Multiple Deprivation, history of pregnancy loss, epilepsy, bipolar and other psychiatric conditions, other somatic conditions. ASM, antiseizure medication.

Figure 3

Association between first-trimester ASM use and miscarriage: results from different analytical methods. Adjusted for maternal age, year of pregnancy start, Index of Multiple Deprivation, epilepsy, bipolar and other psychiatric conditions, other somatic conditions and for analyses excluding the discordant ASM pregnancies, history of pregnancy loss. ASM, antiseizure medication.

Figure 4

HRs of miscarriage associated with specific antiseizure medications in pregnancy, among women with first-trimester ASM exposure, compared with lamotrigine exposure. *Adjusted for: maternal age, year of pregnancy start, Index of Multiple Deprivation, history of pregnancy loss, epilepsy, bipolar, other psychiatric conditions, other somatic conditions. ASM, antiseizure medication.